The present invention relates to ligands useful in forming complexes with radionuclide metal ions to provide materials useful for in vivo diagnostic and therapeutic applications. More specifically, the ligands of the present invention have particular application in the formation of complexes with technetium-99 m.
The use of radionuclide metal ions in therapeutic and in vivo diagnostic applications has been practiced for some time. For example, gamma-emitting radionuclide metal ions, including technetium-99 m, have been used in diagnostic scintigraphy for tumor detection. Beta-emitting isotopes, including rhenium-186, rhenium-188 and rhenium-189, can be used therapeutically in the treatment of tumors. Positron emission tomography may be used for diagnostic imaging and its use for evaluation of regional cerebral and myocardial blood flow is well documented.
Diagnostic nuclear medicine involves the administration to a subject of a radiation-emitting isotope which localizes in the tissues of interest. An image of these tissues then is obtained using a scintillation camera such as an Anger scintillation camera. Tc-99 m is an ideal radioisotope for use in nuclear medicine It has a half-life of 6 hours and a gamma-radiation of 140 keV, with no alpha or beta radiation. It is easily prepared using a Mo-99 m generator and is relatively inexpensive. Finally, its chemistry is such that it can be incorporated into diverse chemical forms in order to image different types of tissues.
Tc-99 m has become widely used for scintillation scanning of bone tissue and infarcted myocardial tissue. In these applications, the Tc-99 m is administered with a carrier such as methanehydroxydiphosphonate and a reducing agent such as SnCl.sub.2. The Tc-99 m diphosphonate complex acts as a calcium-seeking agent which accumulates in bone, particularly at sites of high calcium turnover in newly forming or cancerous bone, and in myocardial infarcts that contain calcium phosphate.
Within the past several years, interest has developed in producing Tc-99 m-based radiodiagnostic agents which will accumulate in normal heart tissue, as opposed to infarcted tissue Such radiodiagnostic agents would be of great benefit inasmuch as they would allow for the early identification of individuals at high risk of having heart attacks.
The efficacy of radionuclides in in vivo diagnostic and therapeutic applications depends on the ability of the ligand-radionuclide complex to deliver the radionuclide to the site of the target cells. Thus, the biodistribution of these imaging compounds may determine their usefulness in various therapeutic or diagnostic applications.
There is a continuing need in the art for ligands which form stable complexes with known radionuclides, particularly, technetium, and which are useful in diagnostic and therapeutic imaging applications. There also is a need in the art for ligand-radionuclide complexes which display good biodistribution when utilized as diagnostic and therapeutic imaging agents.
The use of such ligands in technetium chemistry is more involved than with other radionuclides, such as In-111, Ga-67, Ga-68, Cu-67 and Tl-201. The chemistry of technetium involves a reduction of the starting Tc (VII) oxidation state that is inextricably coupled to the complexing of the reduced technetium with a ligand. For the other radionuclides only the complexing step is necessary as they are provided in the desired oxidation state. This fact makes the chemistry of technetium unique. Because of these differences, it is difficult to predict which of the ligands that can form complexes with indium-111, gallium-67 or -68, or copper -67 also can form complexes with technetium-99 m to provide useful radiodiagnostic agents.
Green, et al., J. Nuclear Med., 26:170-180 (1985), teaches the reaction of tris (acetylacetonato) gallium (III) with 1, 1, 1-tris (5-methoxysalicyl-aldiminomethyl) ethane to produce a neutral six coordinate complex. The gallium complex was tested for its ability as an imaging agent in positron emission tomography. This complex has no overall charge. The images of a dog's heart and the biodistribution data in rats from the compound showed that the compound washed out quickly from the heart, indicative of its neutral character. No further mention of this or other derivatives of this ligand with gallium for use in nuclear medicine have been found in the literature.
It is an object of this invention to provide novel complexes of ligands with technetium which are useful as radiodiagnostic agents. More specifically, it is an object of this invention to provide such complexes which are useful as heart imaging agents. Further objects of the invention will become apparent upon reading the description of the invention and appended claims set forth below.